Lessons Learned and Yet-to-Be Learned on the Importance of RNA Structure in SARS-CoV-2 Replication

Abstract

SARS-CoV-2, the etiological agent responsible for the COVID-19 pandemic, is a member of the virus family Coronaviridae , known for relatively extensive (~30-kb) RNA genomes that not only encode for numerous proteins but are also capable of forming elaborate structures. As highlighted in this review, these structures perform critical functions in various steps of the viral life cycle, ultimately impacting pathogenesis and transmissibility.

CASP15 cryo‐EM protein and RNA targets: Refinement and analysis using experimental maps

“…Maps and reference structures for four alternative conformations of the SL5 domain from 5′UTR from the Bat coronavirus BtCoV‐HKU5 were provided for assessment in this CASP. This domain is known to have a conserved secondary structure in many coronaviruses, 32,33 which is thought to be important in the packaging of viral particles during infection 34 . Maps for this target varied in resolution from 5.6 to 7.6 Å.…”

“…This domain is known to have a conserved secondary structure in many coronaviruses, 32,33 which is thought to be important in the packaging of viral particles during infection. 34 Maps for this target varied in resolution from 5.6 to 7.6 Å. The four refined predictions for the third conformation (R1156v3) exhibited average SMOC values slightly higher than the reference structure.…”

Extracellular Vesicle-Based SARS-CoV-2 Vaccine

“…When the human immune system produces antibodies, it recognizes this spike protein and produces antibodies that match its shape. Inside the sphere is an RNA genome of approximately 30 kb, the largest known RNA viral genome, bound to a protein called nucleocapsid, which consists of the N protein, the most abundant protein in viral particles [ 27 , 28 ]. The outer nucleocapsid is enveloped and consists of lipid membranes, which are easily destroyed by washing with soap and detergent or disinfecting with alcohol, rendering the virus infective.…”

RNA: The most attractive target in recent viral diseases

“…Most of the recently‐evolved highly pathogenic viruses, for example, the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), are RNA in nature (i.e., RNA viruses) (Griffin, 2022; International Committee on Taxonomy of Viruses Executive Committee, 2020). Interestingly, the high attractiveness of the viral RNA in medicinal and therapeutic chemistry comes mainly from, first, its unique ability to encode diverse information and functions (including regulating the virus's own genome replication as well as interacting with host ribosomes) in its sequential structure; second, the slight differences in the biochemical synthetic pathways between the viral and human RNAs (this provides significant beneficial drug selectivity and specificity); third, the high number of highly‐conserved viral enzymes that act on viral RNAs (this provides richness and broadness in drug action); and, fourth, the usual relative long‐term persistence of viral RNAs after acute infection recoveries in humans and other hosts (this provides feasible pathways and choices for tracking and curing the long‐term sequelae of such viral infections/diseases) (Bassett et al., 2022; Griffin, 2022; Rabie, 2022a, 2022b; Rabie et al., 2023).…”